Adrenal failure occurs in approximately 1/10,000 of the adult population and 1/16,000 of infants. It may be due to either primary adrenal failure (e.g. Addison's disease commonly occurring following autoimmune damage to the adrenal gland) or tuberculosis; or secondary adrenal failure which occurs due to pituitary failure which may be caused by a pituitary tumour or surgery. In primary adrenal failure, ACTH levels from the pituitary will be high and in secondary adrenal failure ACTH levels are inappropriately low. Tertiary adrenal failure is another common cause of adrenal failure and leads to suppression of the normal pituitary-adrenal axis by steroid therapy such as that used in chemotherapy, rheumatoid arthritis and asthma. A further condition that results from adrenal failure is glucocorticoid-remediable aldosteronism (GRA) which results from increased secretion of aldosterone. Thus, adrenal failure is a relatively common condition and many patients have to take long-term steroid replacement therapy.
It is apparent that dosing regimens for the treatment of children, adults and elderly adults will vary depending on a number of parameters such as developmental stage and physiological state.
For example, the treatment of children suffering adrenal insufficiency is problematic for a number of reasons and treatment regimens used to treat adult subjects suffering adrenal failure are not equivalent when applied to non-adults [e.g. neonates, infants, small child, and pre-pubescent child]. The treatment of paediatric adrenal insufficiency has particular problems and requires pharmaceutical formulations that address the pharmacokinetic and pharmacodynamic problems of dosing infants. Hepatic microsomal enzyme processes are not fully developed in infants who may require alternative dosage and administration regimens of one, two or more doses of drug. In drugs that are cleared by the liver there is a gradual increase in drug clearance rate throughout childhood to the fully mature adult which once again requires careful monitoring of dose and dosage regimen.
Current preparations of hydrocortisone cannot adequately replace cortisol deficiency especially in the paediatric population because the formulations used do not allow the flexibility of (low) dose hydrocortisone to reproduce physiological levels of cortisol. For example, after diagnosis with adrenal insufficiency, usually at birth, a common dose of hydrocortisone prescribed in the United Kingdom is 7.5 mg per day divided into three equal doses (i.e. 3×2.5 mg per day). However, the smallest hydrocortisone tablet currently available in the United Kingdom and most of Europe is 10 mg hydrocortisone (5 mg hydrocortisone—Cortef® in the US). These tablets are often halved and/or quartered or crushed and repackaged to provide the required dose. Where a 10 mg hydrocortisone tablet is available, the 2.5 mg dose is usually the smallest dose attainable because it is difficult to accurately divide a tablet into more than four quarters. Where a 5 mg hydrocortisone tablet is available, a 1.25 mg dose is usually the smallest dose attainable.
In the United Kingdom, paediatric clinicians and patients believe that the 7.5 mg daily dose is far too high for neonates (0-28 days old), infants (1-24 months old) and young children (2-6 years old) and that the disease is not being adequately controlled but rather over treated. For example overtreatment with glucocorticoids such as hydrocortisone means that children suffer from very poor growth, poor weight-control and metabolic issues through development. One result of this glucocorticoid overtreatment in early childhood is that children never reached their full genetic height potential, suffer from low bone density at puberty (and into adulthood) and are at risk of obesity and a poor metabolic profile with increased cardiovascular risk factors in adult life.
For infants, crushed hydrocortisone tablets can give rise to dosing inconsistency as the poor solubility of the drug requires the use of suspension delivery methods which can lead to dose in homogeneity. Individual case reports have shown poor control of congenital adrenal hyperplasia with either excessive cortisol levels or low cortisol levels in association with poor androgen control after oral administration of crushed tablets. In addition infants and children do not like the taste of hydrocortisone making administration difficult and compliance unreliable. Studies investigating the bio-availability/pharmacokinetics on the stability of these tablets, when divided, have shown suboptimal treatment questioning the efficacy and ethics of such practice, particularly in the most vulnerable patients of all, neonates and infants.
Common problems in delivering hydrocortisone in accordance with levels required for normal and healthy growth in children are that: (a) currently available tablet formulations do not enable accurate, low dose titration of hydrocortisone, (b) such tablet formulations when crushed to facilitate suspension delivery suffer poor dose homogeneity and have only a limited shelf-life (less than 1 month at 4 degrees Centigrade) necessitating refrigerated storage and further complicating end use. Furthermore, if a subject receiving the medication is able to taste the active ingredient upon ingestion they may refuse to comply with the prescribed dosage regimen. This is particularly acute with paediatric and elderly patients who may have problems swallowing tablets or capsules. This is also a problem if multiple dosages are required throughout the day.
It is now increasingly recognised that all patients with adrenal insufficiency are receiving excess glucocorticoid because of the limited ability to dose titrate. This excess glucocorticoid is associated with an increased mortality rate in patients with adrenal insufficiency. In adults optimal treatment requires at least thrice daily dosing with a weight related dose. Total daily doses vary between 10 and 30 mg but as a larger dose is required in the morning current dosage formulations do not allow adequate titration putting patients at risk of either over or under treatment at different times of the day.
In our PCT application [WO2013/072707], we disclose hydrocortisone formulations that are substantially immediate release, are palatable and useful in the treatment of adrenal insufficiency in paediatric patients. The present disclosure relates to a further formulation not disclosed in WO2013/072707 and which has an improved properties. We also disclose regimens that show improved disease control in paediatric or elderly subjects, improved compliance and reduced side effect profile.